Despite much interest in expanding chemical space, diverse, billion molecule libraries remain inaccessible. In principle, docking a virtual library could access some of this missing chemical space. This idea has until now been vitiated by two key problems: 1. prediction of readily synthesized molecules has been challenging, without resorting to strategies that collapse diversity; and 2. docking is notoriously inaccurate. Two recent advances have made virtual library docking screens seem less fanciful. First, our collaborators at Enamine, a widely used fine chemicals supplier, have defined a 0.7 billion molecule make-on-demand library based on >100 reactions that they have under good control; >650,000 of these have been successfully synthesized. Second, while docking retains serious errors, it has made pragmatic progress, and has found genuinely novel ligands for >100 targets. The specific aims are: Aim 1. A robust, searchable, and dockable database of 3 billion diverse lead-like molecules. We will A. Enumerate 3 billion vetted products from two- and three-component reactions. B. measure the diversity and novelty of this library and how they differ from the world's in-stock molecules. C. Develop a community accessible database and chemoinformatics infrastructure that can store, similarity search, and rapidly retrieve molecules from this library. D. convert these molecules into biologically relevant 3D forms, including enumerating low- energy conformers, partial atomic charges and other parameters, van der Waals parameters and solvation energies for all library molecules, enabling their use for docking screens. Aim 2. Dock and experimentally test the library against two targets. A. Screen the library against the dopamine D4 and kappa-opioid receptors, seeking novel ligands. 250 to 500 library molecules will be tested per screen, itself a 10-fold increase. A key question will be do we find novel, potent ligands, or are we overwhelmed by false positives? B. As the library grows, do we continue to find ever more novel, in some sense ever more perfect, high affinity ligands, or does discovery saturate? C. How does hit rate vary with docking score? As we will be testing hundreds of molecules, we can afford to investigate not only those with the highest docking ranks, but also molecules with mediocre and poor ranks. This has not been previously explored, certainly not at scale. If successful, this project will increase the number of molecules available to the community by 1000-fold, and demonstrate their utility for ligand discovery. Extensive preliminary results support its feasibility.